title: Evidence of how rs7575840 influences apolipoprotein B-containing lipid particles.
abstract: OBJECTIVE
  Recent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlying functional mechanism of this variant, which resides 6.5 kb upstream of APOB, has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB-containing lipid particles, for replication in a Mexican population, and for its underlying functional mechanism.
  
  
  RESULTS
  Our data show that rs7575840 is associated with serum apoB levels (P=4.85×10(-10)) and apoB-containing lipid particles, very small very-low-density lipoprotein, intermediate lipoprotein, and LDL particles (P=2×10(-5) to 9×10(-7)) in the Finnish Metabolic Syndrome in Men study sample (n=7710). Fine mapping of the APOB region using 43 single-nucleotide polymorphisms replicated the association of rs7575840 with apoB in a Mexican study sample (n=2666, P=3.33×10(-5)). Furthermore, our transcript analyses of adipose RNA samples from 175 subjects in the Finnish Metabolic Syndrome in Men study indicate that rs7575840 alters expression of APOB (P=1.13×10(-10)) and a regional noncoding RNA (BU630349) (P=7.86×10(-6)) in adipose tissue.
  
  
  CONCLUSIONS
  It has been difficult to convert genome-wide association study associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB-containing lipid particles, as well as influencing expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant single-nucleotide polymorphism, rs7575840, may affect serum apoB, LDL cholesterol, and total cholesterol levels.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, Gonda Center, Rm 6335B, 695 Charles E. Young Dr S, Los Angeles, CA 90095-7088, USA.
authors.forename: Blake E
authors.initials: BE
authors.lastname: Haas
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.forename: Elina
authors.initials: E
authors.lastname: Nikkola
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.forename: Ivette
authors.initials: I
authors.lastname: Cruz-Bautista
authors.forename: Laura
authors.initials: L
authors.lastname: Riba
authors.forename: Alena
authors.initials: A
authors.lastname: Stancakova
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
authors.forename: Teresa
authors.initials: T
authors.lastname: Tusie-Luna
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000368:Aged; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood; D005387:Finland / Q000453:epidemiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D007198:Indians, North American / Q000235:genetics; D016014:Linear Models; D053419:Lipoproteins, IDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D008800:Mexico / Q000453:epidemiology; D008875:Middle Aged; D010316:Particle Size; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D044465:White People / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D015415:Biomarkers; D008078:Cholesterol, LDL; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides